Substituted tricyclic derivatives

ABSTRACT

Compounds of formula (I): 
                         
wherein:
     Z, R1, R2, R3, n, and m are as defined in the disclosure. Also disclosed are methods of preparing the compounds of formula (I) and their use in therapeutics.

This application is a continuation of International Application No.PCT/IB2009/006553, filed Jun. 25, 2009, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofEuropean Patent Application No. 08290616.5 filed Jun. 26, 2008.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK3β resultsin a loss of its kinase activity, and it has been hypothesized that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation by GSK3β of β-catenin, a protein involved incell survival, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as p53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseasesand other pathologies where GSK3β is deregulated (Nature reviews Vol. 3,June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9,September 2004, p. 471-480; Journal of neurochemistry 2004, 89,1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).

The neurodegenerative diseases include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease (The Journal ofbiological chemistry Vol. 277, No. 37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Biochem. J. 372, p. 129-136, 2003)and other dementia including vascular dementia; acute stroke and othertraumatic injuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis (European Journal of Neuroscience, Vol. 22, pp. 301-309, 2005)peripheral neuropathies; retinopathies and glaucoma. Recent studies havealso shown that inhibition of GSK3β results in neuronal differentiationof embryonic stem cells (ESC) and support the renewal of human and mouseESCs and the maintenance of their pluripotency. This suggests thatinhibitors of GSK3β could have applications in regenerative medicine(Nature Medicine 10, p. 55-63, 2004).

Inhibitors of GSK3β may also find application in the treatment of othernervous system disorders, such as bipolar disorders (manic-depressiveillness). For example lithium has been used for more than 50 years as amood stabilizer and the primary treatment for bipolar disorder. Thetherapeutic actions of lithium are observed at doses (1-2 mM) where itis a direct inhibitor of GSK3β. Although the mechanism of action oflithium is unclear, inhibitors of GSK3β could be used to mimic the moodstabilizing effects of lithium. Alterations in Akt-GSK3β signaling havealso been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3β could be useful in treating cancers,such as colorectal, prostate, breast, non-small cell lung carcinoma,thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.For example, the active form of GSK3β has been shown to be elevated inthe tumors of colorectal cancer patients and inhibition of GSK3β incolorectal cancer cells activates p53-dependent apoptosis andantagonises tumor growth. Inhibition of GSK3β also enhancesTRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also playsa role in the dynamics of the mitotic spindle and inhibitors of GSK3βprevent chromosome movement and lead to a stabilization of microtubulesand a prometaphase-like arrest that is similar to that observed with lowdoses of Taxol. Other possible applications for GSK3β inhibitors includetherapy for non-insulin dependent diabetes (such as diabetes type II),obesity and alopecia.

Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog of thisenzyme found in Plasmodium falciparum, as a consequence they could beused for the treatment of malaria (Biochimica et Biophysica Acta 1697,181-196, 2004).

Recently, both human genetics and animal studies have pointed out therole of Wnt/LPR5 pathway as a major regulator of bone mass accrual.Inhibition of GSK3β leads to the consequent activation of canonical Wntsignalling. Because deficient Wnt signalling has been implicated indisorders of reduced bone mass, GSK3β inhibitors may also be used fortreating disorders of reduced bone mass, bone-related pathologies,osteoporosis.

According to recent data, GSK3β inhibitors might be used in thetreatment or prevention of Pemphigus vulgaris.

Recent studies show that GSK3beta inhibitor treatment improvesneutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitorswill be useful for the treatment of neutropenia induced by cancerchemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, aelectrophysiological correlate of memory consolidation, suggesting thatinhibitor of this enzyme may have procognitive activity. Procognitiveeffects of the compound could find application for the treatment ofmemory deficits characteristic of Alzheimer's disease, Parkinsondisease, age-associated memory impairment, mild cognitive impairment,brain trauma, schizophrenia and other conditions in which such deficitsare observed.

Inhibitors of GSK3β may also find application in the treatment ofparenchymal renal diseases (Nelson P J, Kidney International Advanceonline publication 19 Dec. 2007) and in the prevention or treatment ofmuscle atrophy (J. Biol. Chem. (283) 2008, 358-366).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides as an object of the invention thetricyclic derivatives represented by formula (I) or salts thereof,solvates thereof or hydrates thereof:

wherein:

-   Z represents a bond, a carbonyl group, a methylene group optionally    substituted by one or two groups chosen from a C₁₋₆ alkyl group, a    hydroxyl group, a C₁₋₆ alkoxy group;-   R1 represents a 4-pyridine ring, a 4-pyrimidine ring;-   R2 represents a hydrogen atom;-   R3 represents:    -   a hydrogen atom;    -   a phenyl or a naphthyl group, these groups being optionally        substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl        group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃        halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group;        a C₁₋₂ perhalogenated alkoxy group, a C₁₋₆ alkylsulfonyl group,        a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group or a        C₂₋₁₂ dialkylamino group, an acetoxy group, an aminosulfonyl        group, a heterocyclic group, this heterocyclic group being        optionally substituted by a C₁₋₆ alkyl group, a halogen atom, a        C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,        a hydroxyl group, a C₁₋₆ alkoxy group;    -   a 5, 6 or 5-6 membered heteroaromatic group, this group being        optionally substituted by 1 to 4 substituents selected from a        C₁₋₆ alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl        group, a C₁₋₆ halogenated alkyl group, a hydroxyl group, a C₁₋₆        alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, a cyano,        an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylamino        group, a S—(C₁₋₆-alkyl) group, a C(O)O(C₁₋₆-alkyl), a        C(O)O(phenyl) group;-   n represents 0 to 3;-   m represents 0 to 1;    with the proviso that the compound of formula (I) wherein n and m    represent 0, z represents a bond, R2 and R3 represent a hydrogen    atom and R1 represents a 4-pyridine ring is not included; in form of    a free base or of an addition salt with an acid.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the tricyclic derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;malaria, bipolar disorders (manic depressive illness); schizophrenia;alopecia or cancers such as colorectal, prostate, breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukaemia,several virus-induced tumours and bone related pathologies; thetreatment of parenchymal renal diseases and in the prevention ortreatment of muscle atrophy; the treatment of cognitive and memorydeficit. The medicament could also find an application in regenerativemedicine.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the diseases are neurodegenerativediseases and are selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, tauopathies (e.g. Fronto temporaldementia, corticobasal degeneration, Pick's disease, progressivesupranuclear palsy), Wilson's disease, Huntington's disease, Priondisease and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis; peripheral neuropathies; retinopathies and glaucoma, and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the bones related pathologies areosteoporosis. The present invention further provides an inhibitor ofGSK3β activity comprising as an active ingredient a substance selectedfrom the group consisting of the tricyclic derivatives of formula (I)and the salts thereof, and the solvates thereof and the hydratesthereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of tricyclic derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the tricyclic derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedor cyclo alkyl group having 1 to 6 carbon atoms, optionally substitutedby a straight, branched or cyclic C₁₋₆ alkyl group, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexylgroup, isohexyl group, cyclopropylmethyl group and the like.

The heterocyclic group represents a piperidine, pyrrolidine, piperazine,morpholine.

The 5, 6 or 5-6 membered heteroaromatic group represents an aromaticgroup containing 1 to 4 nitrogens. Examples of 5, 6 or 5-6 memberedheteroaromatic group include pyrrole, furan, thiophene, pyrazole,imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole,thiazole, isothiazole, thiadiazolepyridine, pyrimidine, pyrazine,pyridazine, triazine, indole, benzofuran, benzothiophene,pyrrolopyridine, furopyridine, isoindole, isobenzofuran,benzo[c]thiophene, imidazopyridine, furopyrimidine, benzimidazole,pyrazolopyridine, furopyrazine, indazole, triazolopyridine,furopyridazine, indolizine, tetrazolopyridine, furotriazine,pyrrolopyrimidine, oxazolopyridine, imidazopyrimidine,oxazolopyrimidine, pyrazolopyrimidine, oxazolopyrazine,triazolopyrimidine, oxazolopyridazine, tetrazolopyrimidine,oxazolotriazine, pyrrolopyrazine, isoxazolopyridine, imidazopyrazine,isoxazolopyrimidine, pyrazolopyrazine, Isoxazolopyrazine,triazolopyrazine, isoxazolopyridazine, tetrazolopyrazine,isoxazolotriazine, pyrrolopyridazine, oxadiazolopyridine,imidazopyridazine, oxadiazolopyrimidine, pyrazolopyridazine,oxadiazolopyrazine, triazolopyridazine, oxadiazolopyridazine,tetrazolopyridazine, oxadiazolotriazine, pyrrolotriazine, benzoxazole,imidazotriazine, benzisoxazole, pyrazolotriazine, benzoxadiazole,triazolotriazine, tetrazolotriazine, thienopyridine, thienopyrimidine,thienopyrazine, thienopyridazine, thienotriazine, thiazolopyridine,thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine,thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine,isothiazolopyrazine, isothiazolopyridazine, isothiazolotriazine,thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyrazine,thiadiazolopyridazine, thiadiazolotriazine, benzothiazole,benzisothiazole, benzothiadiazole

The C₁₋₆ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen atoms have been substituted by a halogeno, for examplea CF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast, one hydrogen has not been substituted by a halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group, isopentylamino groupand the like;

The C₂₋₁₂ dialkylamino group represents an amino group substituted bytwo C₁₋₆ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group and the like;

A leaving group L represents a group which could be easily cleaved andsubstituted; such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid; salts with organic acidssuch as acetic acid, propionic acid, tartaric acid, fumaric acid, maleicacid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acidand the like.

The acid-addition salts of the basic compounds are prepared by standardprocedures well known in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the tricyclic derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The tricyclic derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be either in (R)or (S) configuration, and the derivative may exist as stereoisomers suchas optical isomers, or diastereoisomers. Any stereoisomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

In a first embodiment of the invention, there is provided compoundswherein:

-   Z represents a bond, a C₁₋₃ alkyl group, a carbonyl group, a    methylene group optionally substituted by one or two groups chosen    from a hydroxyl group;-   R1 represents a 4-pyridine ring, a 4-pyrimidine;-   R2 represents a hydrogen atom;-   R3 represents:    -   a phenyl being optionally substituted by 1 to 4 substituents        selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂        perhalogenated alkyl group, a C₁₋₆ alkoxy group; a C₁₋₂        perhalogenated alkoxy group, a cyano, a piperidine, a        pyrrolidine being optionally substituted by a C₁₋₆ alkyl group;    -   a 5, 6 or 5-6 membered heteroaromatic group;-   n represents 0 to 3;-   m represents 0 to 1, in form of a free base or of an addition salt    with an acid.

In a second embodiment of the invention, there is provided compoundswherein

-   Z represents a bond, a C₁₋₃ alkyl group, a carbonyl group, a    methylene group optionally substituted by one or two groups chosen    from a hydroxyl group;-   R1 represents a 4-pyridine ring, 4-pyrimidine ring;-   R2 represents a hydrogen atom;-   R3 represents:    -   a phenyl being optionally substituted by 1 to 4 substituents        selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂        perhalogenated alkyl group, a C₁₋₆ alkoxy group; a C₁₋₂        perhalogenated alkoxy group, a cyano, a piperidine, a        pyrrolidine being optionally substituted by a C₁₋₆ alkyl group;    -   a pyridine, an indole, an imidazopyridine, a pyrrole;-   n represents 0 to 3;-   m represents 0 to 1, in form of a free base or of an addition salt    with an acid.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds. The nomenclature is given according to IUPAC rules.

A further object of the present invention includes the group ofcompounds of table 1 of formula as defined hereunder:

-   -   1.        9-[3-(2-Fluoro-phenyl)-propyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   2.        9-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   3.        9-(2-Oxo-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   4.        (—)-9-((S)-2-Hydroxy-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   5.        9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   6.        9-(2-Phenylethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   7.        9-{2-[3-(4-Methyl-piperazin-1-yl)-phenyl]-2-oxo-ethyl}-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   8.        9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   9.        9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   10.        9-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   11.        9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   12.        9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   13.        9-(2-Oxo-2-pyridin-3-yl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   14.        9-[2-Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   15.        9-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   16.        9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   17.        9-[2-Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   18.        3-[2-(4-Oxo-2-pyridin-4-yl-4H,10H-1,4a,9-triaza-anthracen-9-yl)-acetyl]-benzonitrile    -   19.        9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   20.        9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   21.        9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   22.        3-[2-(4-Oxo-2-pyrimidin-4-yl-4H,10H-1,4a,9-triaza-anthracen-9-yl)-acetyl]-benzonitrile    -   23.        9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   24.        9-[2-(3,5-Difluoro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   25.        9-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   26.        9-[2-Oxo-2-(3-trifluoromethoxy-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   27.        9-[2-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   28.        9-[2-(3,5-Difluoro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   29.        9-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   30.        9-[2-Oxo-2-(3-trifluoromethoxy-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   31.        9-(2-Oxo-2-pyridin-4-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   32.        9-(2-Oxo-2-pyridin-3-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   33.        9-(2-Oxo-2-pyridin-2-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   34.        9-(2-Oxo-2-pyridin-4-yl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   35.        9-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   36.        9-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   37.        9-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   38.        9-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   39.        9-[2-(4-Fluoro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   40.        9-[2-(4-Fluoro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   41.        9-[2-(3-Fluoro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   42.        9-[2-(3-Chloro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   43.        9-[2-(3-Fluoro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   44.        9-[2-(3-Chloro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   45.        2-Pyridin-4-yl-9-(2-pyridin-2-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   46.        9-(2-Pyridin-2-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   47.        2-Pyridin-4-yl-9-(2-pyrrol-1-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   48.        2-Pyridin-4-yl-9-(3-pyrrol-1-yl-propyl)-9,10-dihydro-1,4-a,9-triaza-anthracen-4-one    -   49.        2-Pyrimidin-4-yl-9-(2-pyrrol-1-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   50.        2-Pyrimidin-4-yl-9-(3-pyrrol-1-yl-propyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   51.        9-Imidazo[1,2-a]pyridin-2-ylmethyl-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   52.        (—)-9-((S)-2-Hydroxy-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    -   53.        10-(3-Phenyl-propyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one    -   54.        10-[2-(1H-Indol-3-yl)-ethyl]-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one    -   55.        10-(2-Phenyl-ethyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one    -   56.        10-(4-Phenyl-butyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one    -   57.        10-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one

As a further object, the present invention concerns also methods forpreparing the tricyclic compounds represented by the aforementionedformula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Tricyclic compounds represented by the aforementioned formula (I), maybe prepared according to the method described in the scheme 1.

(In the above scheme the definition of R1, R2, R3, n, m and Z are thesame as those already described for compound of formula (I)).

The tricyclic derivative represented by the above formula (III), whereinm, R1 and R2 are as defined for compound of formula (I), is allowed toreact with a base such as sodium hydride, sodium carbonate or potassiumcarbonate in a solvent such as N,N-dimethylformamide,N-methylpyrrolidine, N,N-dimethylacetamide or chloroform at a suitabletemperature ranging from 0 to 130° C. under ordinary air, then with acompound of formula (II), wherein R3, Z and n are as defined forcompound of formula (I) and L represents a leaving group preferablybromide or mesyloxy group, is added to obtain the compound of theaforementioned formula (I).

Compound of formula (II) are commercially available or may besynthesized according to well-known methods of one skilled in the art.The compound of formula (III) may be prepared according to the methoddefined in scheme 2.

According to this method, the 3-ketoester of formula (IV) is allowed toreact with a compound of formula (V). The reaction may be carried out inthe presence of potassium carbonate, in a alcoholic solvent such asmethanol, ethanol and the like or without, at a suitable temperatureranging from 25° C. to 140° C. under ordinary air.

Alternatively, compounds of formula (III) wherein R2 represents ahydrogen atom may be halogenated in order to give compounds of formula(III) wherein R2 is an halogen atom such as a bromine atom or a chlorineatom.

The reaction may be carried out in an acidic medium such as acetic acidor propionic acid, in presence of bromosuccinimide or chlorosuccinimide,or bromine.

In addition, compounds of formula (III) wherein R2 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

Compounds of formula (V) or (IV) are commercially available or may besynthesized according to well-known methods of one skilled in the art.

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. Fronto temporal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy), Wilson's disease, Huntington'sdisease, Prion disease and other dementia including vascular dementia;acute stroke and others traumatic injuries; cerebrovascular accidents(e.g. age related macular degeneration); brain and spinal cord trauma;amyotrophic lateral sclerosis, peripheral neuropathies; retinopathiesand glaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; malaria, manic depressiveillness; schizophrenia; alopecia; cancers such as colorectal, prostatebreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia, several virus-induced tumours and in bone relatedpathologies; parenchymal renal diseases or muscle atrophy. Themedicament could also find an application in regenerative medicine. Themedicament could also find an application in the treatment or preventionof Pemphigus vulgaris. The medicament could also find an application inthe treatment of neutropenia induced by cancer chemotherapy. Themedicament could also find an application for therapeutic treatment of adisease characterized by cognitive and memory deficits such as inAlzheimer's disease, Parkinson disease, age associated memoryimpairment, mild cognitive impairment, brain trauma, schizophrenia andother conditions in which such deficits are observed.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention; however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound No. 2 of Table 1

-   9-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    Hydrochloride (1:1)-   1.1 2-Pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one

To a suspension of 6.00 g (26.31 mmol) of1,4-dihydro-quinazolin-2-ylamine monohydrobromide (synthesis asdescribed in Chemical & Pharmaceutical Bulletin (1980), 28(5), 1357-64.)in 53 mL of ethanol was added 7.27 g (52.61 mmol) of potassiumcarbonate. The reaction mixture was stirred at room temperature for 10min, 4.88 g (25.25 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate wasadded and the resulting mixture was stirred under reflux for 18 hours.The cooled solution was evaporated to remove solvent, water was addedand the precipitate filtered. The resulting solid was washed withmethanol and diethyl ether to afford 1.42 g (20%) of the desiredcompound as a white powder.

MP: 315-317° C.

RMN¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 10.65 (brs, 1H), 8.70 (d, 2H), 7.90 (d, 2H), 7.20 (m, 2H), 7.00(m, 2H), 6.60 (s, 1H), 5.10 (s, 2H).

-   1.2    9-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one    Hydrochloride (1:1)

To a solution of 0.4 g (1.45 mmol) of2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one in 12 ml ofanhydrous dimethylformamide was added 0.075 g (1.88 mmol) of sodiumhydride (60% suspension in mineral oil) and the mixture allowed to stirat 50° C. for 1 h. The mixture was cooled at 0° C., 0.375 g (1.88 mmol)of 2-bromo-1-phenyl-ethanone was added and stirring continued at roomtemperature for 12 h.

Water was added and the mixture extracted with chloroform. The extractswere washed with a saturated aqueous solution of sodium chloride, driedand evaporated to give crude product. Purification by chromatography onsilica gel eluting with a mixture of dichloromethane/methanol/ammonia inthe proportions 95/5/0.5 gave 0.345 g (61%) of pure product which wastransformed into the hydrochloride salt in the usual manner to give0.297 g (79%) of pure product as a white solid.

Mp.: 258-260° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.70 (d, 2H), 8.10 (m, 4H), 7.70 (d, 1H), 7.60 (m, 2H), 7.40(d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 6.90 (s, 1H), 5.80(s, 2H), 5.20 (s, 2H).

Example 2 Compound No. 3 of Table 1

-   9-(2-Oxo-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one-   2.1 2-Pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one

By analogy with the method described in example 1 (step 1.1), using3-oxo-3-pyrimidin-4-yl-propionic acid ethyl ester in place of ethyl3-(4-pyridinyl)-3-oxopropionate, 3.80 g (17%) of the compound wasobtained as a powder.

Mp: 290-292° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 9.30 (s, 1H), 9.00 (d, 1H), 8.15 (d, 1H), 7.25 (m, 2H), 7.00(d, 2H), 6.80 (s, 1H), 5.10 (s, 2H).

-   2.2    9-(2-Oxo-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one

By analogy with the method described in example 1 (step 1.2), using2-pyrimidin-4-yl-9,10-dihydro-1,4-a,9-triaza-anthracen-4-one in place of2-Pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one, 0.185 g (65%)of the compound was obtained as a powder.

Mp: 263-265° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 9.20 (s, 1H), 8.70 (d, 1H), 8.15 (d, 2H), 7.80-7.50 (m, 4H),7.40 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 6.90 (s, 1H),5.80 (s, 2H), 5.20 (s, 2H).

Example 3 Compound No. 53 of Table 1

-   10-(3-Phenyl-propyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2a]pyrimidin-4-one    maleate (1:1)-   3.1 2-Pyridin-4-yl-10H-benzo[4,5]imidazo[1,2a]pyrimidin-4-one

3.00 g (20.0 mmol) of 2-aminobenzimidazole and 8.50 g (44.0 mmol) ofethyl 3-(4-pyridinyl)-3-oxopropionate were added to 26 g ofpolyphosphoric acid (84% min.). The reaction mixture was heated at 130°C. for 18 hours. The residue was dissolved in cooled water and theresulting precipitate filtered. The solid was washed with hot ethanoland dried to give 3.35 g (64%) of pure product.

Mp: 300-302° C.

RMN ¹H (DMSO; 200 MHz)

δ (ppm): 8.80 (d, 2H), 8.50 (d, 1H), 8.15 (d, 2H), 7.60 (d, 2H), 7.40(m, 1H), 6.80 (s, 1H)

-   3.2    10-(3-Phenyl-propyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one    maleate (1:1)

To a suspension of 0.3 g (1.14 mmol) of2-Pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one in 5 mL ofdimethylformamide was added 0.174 g (1.26 mmol) of potassium carbonate.The reaction mixture was stirred at room temperature for 10 min, 191 μl(1.26 mmol) of 1-bromo-3-phenylpropane was added and the resultingmixture was stirred at 130° C. for 1 H. Water was added and the mixtureextracted with ethyl acetate. The extracts were washed with a saturatedaqueous solution of sodium chloride, dried and evaporated to give crudeproduct. Purification by chromatography on silica gel eluting with amixture of dichloromethane/methanol/ammonia in the proportions 95/5/0.5gave 0.167 g (39%) of pure product which was transformed into themaleate salt in the usual manner.

Mp: 208-210° C.

RMN ¹H (DMSO; 200 MHz)

δ (ppm): 8.80 (d, 2H), 8.50 (d, 1H), 8.10 (d, 2H), 7.80 (d, 1H), 7.60(dd, 1H), 7.40 (dd, 1H), 7.20 (m, 5H), 6.90 (s, 1H), 6.20 (s, 2H), 4.50(t, 2H), 2.75 (t, 2H), 2.20 (m, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1. The compounds have been prepared according to the methods ofthe examples.

In the table, R2 represents H, Ph represents a phenyl group, Merepresents a methyl group, (Rot.) indicates the levorotatory ordextrorotatory properties of the enantiomeric compound, (dec.) indicatesthe decomposition of the compound.

TABLE 1 Mp ° C./ No. Rot R3 Z R1 m n alpha D salt  1

CH₂

1 2 208-210 Maleate (1:1)  2 Ph CO

1 1 258-260 Hydrochloride (1:1)  3 Ph CO

1 1 263-265 Free base  4 (−) Ph CH(OH)(S)

1 1 275-276 Alpha D = −32.3° (c = 0.613 g/100 ml; DMSO) Hydrochloride(1:1)  5

CO

1 1 282-285 Free base  6 Ph CH₂

1 1 179-181 Free base  7

CO

1 1 256-258 Free base  8

CO

1 1 267-270 Hydrochloride (1:1)  9

CO

1 1 242-245 Free base 10

CO

1 1 260-263 Hydrochloride (1:1) 11

CO

1 1 298-301 Hydrochloride (1:1) 12

CO

1 1 262-265 Hydrochloride (1:1) 13

CO

1 1 267-270 Hydrochloride (1:2) 14

CO

1 1 306-309 Hydrochloride (1:2) 15

CO

1 1 390-393 Free base 16

CO

1 1 291-294 Free base 17

CO

1 1 307-310 Free base 18

CO

1 1 323-325 Free base 19

CO

1 1 266-268 Free base 20

CO

1 1 269-271 Free base 21

CO

1 1 296-298 Free base 22

CO

1 1 318-320 Free base 23

CO

1 1 281-283 Free base 24

CO

1 1 353-356 Free base 25

CO

1 1 228-231 Free base 26

CO

1 1 253-256 Free base 27

CO

1 1 210-213 Free base 28

CO

1 1 261-264 Free base 29

CO

1 1 228-230 Free base 30

CO

1 1 259-262 Free base 31

CO

1 1 260-263 Free base 32

CO

1 1 260-262 Free base 33

CO

1 1 245-248 Free base 34

CO

1 1 257-259 Free base 35

CO

1 1 342-344 Free base 36

CO

1 1 264-266 Free base 37

CO

1 1 234-237 Free base 38

CO

1 1 282-285 Free base 39

CH₂

1 1 210-212 Free base 40

CH₂

1 1 215-217 Free base 41

CH₂

1 1 181-190 Free base 42

CH₂

1 1 184-187 Free base 43

CH₂

1 1 175-179 Free base 44

CH₂

1 1 193-195 Free base 45

CH₂

1 1 187-189 Free base 46

CH₂

1 1 185-188 Free base 47

CH₂

1 1 178-180 Free base 48

CH₂

1 2 173-175 Free base 49

CH₂

1 1 156-158 Free base 50

CH₂

1 2 227-230 Free base 51

bond

1 0 366-369 Free base 52 (−) Ph CH(OH)(S)

1 1 194-195 Alpha D = −31.4° (c = 0.654 g/100 ml; DMSO) Free base 53 PhCH₂

0 2 208-210 Maleate (1:1) 54

CH₂

0 1 205-207 Free base 55 Ph CH₂

0 1 210-212 Maleate (1:1) 56 Ph CH₂

0 3 230-232 Hydrochloride (1:1) 57 Ph CO

0 1 290-292 Hydrochloride (1:1)

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Four different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm ³³P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta.

In a third protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for onehour at room temperature in the presence of GSK3beta (total reactionvolume: 100 microliters).

In a fourth protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for 90minutes at room temperature in the presence of commercial GSK3beta(Millipore) (total reaction volume: 100 microliters).

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry. The phosphorylated GS-1 peptidehad the following sequence: NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett, J. R. (1989) Analytical Biochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 are between 0.1 nanomolar to 3 micromolarconcentrations.

For example, on the protocol 3, the compound No. 3 of table 1 shows anIC₅₀ of 0.006 μM and the compound No. 58 of table 1 shows an IC₅₀ of0.0005 μM.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg(3) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A compound of formula (I):

wherein: Z represents a bond, a carbonyl group, or a methylene groupoptionally substituted by one or two groups chosen from a C₁₋₆ alkylgroup, a hydroxyl group, and a C₁₋₆ alkoxy group; R1 represents a4-pyridine ring or a 4-pyrimidine ring; R2 represents a hydrogen atom;R3 represents: a hydrogen atom; a phenyl or a naphthyl group, thesegroups being optionally substituted by 1 to 4 substituents selected froma C₁₋₆ alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, aC₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, aC₁₋₂ perhalogenated alkoxy group, a C₁₋₆ alkylsulfonyl group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylaminogroup, an acetoxy group, an aminosulfonyl group, and a heterocyclicgroup, this heterocyclic group being optionally substituted by a C₁₋₆alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group, a hydroxyl group, or a C₁₋₆ alkoxy group; or a5, 6 or 5-6 membered heteroaromatic group, this group being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆ halogenatedalkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₆ halogenatedalkoxy group, a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group, aC₂₋₁₂ dialkylamino group, a S—(C₁₋₆-alkyl) group, a C(O)O(C₁₋₆-alkyl),and a C(O)O(phenyl) group; n represents 0 to 3; and m represents 0 to 1;with the proviso that the compound of formula (I) wherein n and mrepresent 0, Z represents a bond, R2 and R3 represent a hydrogen atomand R1 represents a 4-pyridine ring is not included; or an acid additionsalt thereof.
 2. A compound of formula (I):

wherein: Z represents a bond, a C₁₋₃ alkyl group, a carbonyl group, or amethylene group optionally substituted by one or two groups chosen froma hydroxyl group; R1 represents a 4-pyridine ring or a 4-pyrimidine; R2represents a hydrogen atom; R3 represents: a phenyl being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆ alkoxy group, aC₁₋₂ perhalogenated alkoxy group, a cyano, a piperidine, or apyrrolidine being optionally substituted by a C₁₋₆ alkyl group, or a 5,6 or 5-6 membered heteroaromatic group; n represents 0 to 3; mrepresents 0 to 1; or an acid addition salt thereof.
 3. The compound offormula (I) according to claim 2:

wherein: Z represents a bond, a C₁₋₃ alkyl group, a carbonyl group, amethylene group optionally substituted by one or two groups chosen froma hydroxyl group; R1 represents a 4-pyridine ring or 4-pyrimidine ring;R2 represents a hydrogen atom; R3 represents: a phenyl being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆ alkoxy group, aC₁₋₂ perhalogenated alkoxy group, a cyano, a piperidine, or apyrrolidine being optionally substituted by a C₁₋₆ alkyl group, or apyridine, an indole, an imidazopyridine, or a pyrrole; n represents 0 to3; and m represents 0 to 1; or an acid addition salt thereof.
 4. Thecompound according to claim 1 selected from the group consisting of:9-[3-(2-Fluoro-phenyl)-propyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;(—)-9-((S)-2-Hydroxy-2-phenyl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Phenylethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-{2-[3-(4-Methyl-piperazin-1-yl)-phenyl]-2-oxo-ethyl}-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-pyridin-3-yl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;3-[2-(4-Oxo-2-pyridin-4-yl-4H,10H-1,4a,9-triaza-anthracen-9-yl)-acetyl]-benzonitrile;9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;3-[2-(4-oxo-2-pyrimidin-4-yl-4H,10H-1,4a,9-triaza-anthracen-9-yl)-acetyl]-benzonitrile;9-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3,5-Difluoro-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(3-trifluoromethoxy-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4-a,9-triaza-anthracen-4-one;9-[2-(3,5-Difluoro-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-Oxo-2-(3-trifluoromethoxy-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-pyridin-4-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-pyridin-3-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-pyridin-2-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Oxo-2-pyridin-4-yl-ethyl)-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Fluoro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(4-Fluoro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Chloro-phenyl)-ethyl]-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Fluoro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-[2-(3-Chloro-phenyl)-ethyl]-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;2-Pyridin-4-yl-9-(2-pyridin-2-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-(2-Pyridin-2-yl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;2-Pyridin-4-yl-9-(2-pyrrol-1-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;2-Pyridin-4-yl-9-(3-pyrrol-1-yl-propyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;2-Pyrimidin-4-yl-9-(2-pyrrol-1-yl-ethyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;2-Pyrimidin-4-yl-9-(3-pyrrol-1-yl-propyl)-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;9-Imidazo[1,2-a]pyridin-2-ylmethyl-2-pyridin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;(—)-9-((S)-2-Hydroxy-2-phenyl-ethyl)-2-pyrimidin-4-yl-9,10-dihydro-1,4a,9-triaza-anthracen-4-one;10-(3-Phenyl-propyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one;10-[2-(1H-Indol-3-yl)-ethyl]-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one;10-(2-Phenylethyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one;10-(4-Phenyl-butyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one;and10-(2-Oxo-2-phenyl-ethyl)-2-pyridin-4-yl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one;or an acid addition salt thereof.
 5. A compound represented by formula(III):

wherein: m, R1 and R2 are as defined for compound of formula (I)according to claim 1; with the proviso that the compound of formula(III) wherein m represents 0, R2 represents a hydrogen atom, and R1represents a 4-pyridine ring is not included.
 6. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 1 ora pharmaceutically acceptable salt thereof and one or morepharmaceutical additives.
 7. A pharmaceutical composition comprising acompound of formula (I) according to claim 2 or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutical additives.
 8. Apharmaceutical composition comprising a compound of formula (I)according to claim 3 or a pharmaceutically acceptable salt thereof andone or more pharmaceutical additives.
 9. A pharmaceutical compositioncomprising a compound according to claim 4 or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutical additives.